Covert Consciousness in Acute Brain Injury Revealed by Automated Pupillometry and Cognitive Paradigms.

BACKGROUND: Identifying covert consciousness in intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC) is crucial for treatment decisions, but sensitive low-cost bedside markers are missing. We investigated whether automated pupillometry combined with passive and active cognitive paradigms can detect residual consciousness in ICU patients with DoC. METHODS: We prospectively enrolled clinically low-response or unresponsive patients with traumatic or nontraumatic DoC from ICUs of a tertiary referral center. Age-matched and sex-matched healthy volunteers served as controls. Patients were categorized into clinically unresponsive (coma or unresponsive wakefulness syndrome) or clinically low-responsive (minimally conscious state or better). Using automated pupillometry, we recorded pupillary dilation to passive (visual and auditory stimuli) and active (mental arithmetic) cognitive paradigms, with task-specific success criteria (e.g., ≥ 3 of 5 pupillary dilations on five consecutive mental arithmetic tasks). RESULTS: We obtained 699 pupillometry recordings at 178 time points from 91 ICU patients with brain injury (mean age 60 ± 13.8 years, 31% women, and 49.5% nontraumatic brain injuries). Recordings were also obtained from 26 matched controls (59 ± 14.8 years, 38% women). Passive paradigms yielded limited distinctions between patients and controls. However, active paradigms enabled discrimination between different states of consciousness. With mental arithmetic of moderate complexity, ≥ 3 pupillary dilations were seen in 17.8% of clinically unresponsive patients and 50.0% of clinically low-responsive patients (odds ratio 4.56, 95% confidence interval 2.09-10.10; p < 0.001). In comparison, 76.9% healthy controls responded with ≥ 3 pupillary dilations (p = 0.028). Results remained consistent across sensitivity analyses using different thresholds for success. Spearman's rank analysis underscored the robust association between pupillary dilations during mental arithmetic and consciousness levels (rho = 1, p = 0.017). Notably, one behaviorally unresponsive patient demonstrated persistent command-following behavior 2 weeks before overt signs of awareness, suggesting prolonged cognitive motor dissociation. CONCLUSIONS: Automated pupillometry combined with mental arithmetic can identify cognitive efforts, and hence covert consciousness, in ICU patients with acute DoC.

The Pupillary Light-Off Reflex in Acute Disorders of Consciousness.

BACKGROUND: In intensive care patients with disorders of consciousness, the pupillary light reflex is a measure of pupillary parasympathetic function. By contrast, the pupillary light-off reflex leads to pupil dilation in response to an abrupt change from light to darkness ("light-off") and reflects combined parasympathetic and sympathetic pupillary function. To our knowledge, this reflex has not been systematically investigated in patients with disorders of consciousness. We hypothesized that the pupillary light-off reflex correlates with consciousness levels after acute brain injury. METHODS: From November 2022 to March 2023, we enrolled 100 study participants: 25 clinically unresponsive (coma or unresponsive wakefulness syndrome) and 25 clinically low-responsive (minimally conscious state or better) patients from the intensive care units of a tertiary referral center, and 50 age-matched and sex-matched healthy controls. Exclusion criteria were active or chronic eye disease. We used automated pupillometry to assess the pupillary light-off reflex and the pupillary light reflex of both eyes under scotopic conditions in all study participants. RESULTS: The pupillary light-off reflex was strongly correlated with consciousness levels (r = 0.62, p < 0.001), the increase in pupillary diameters being smallest in unresponsive patients (mean ± standard deviation 20% ± 21%), followed by low-responsive patients (mean ± standard deviation 47% ± 26%) and healthy controls (mean ± standard deviation 67% ± 17%; p < 0.001). Similar yet less pronounced patterns were observed for the pupillary light reflex. Twenty-one of 25 (84%) unresponsive patients had preserved pupillary light reflexes, but only seven (28%) had fully preserved pupillary light-off reflexes (p < 0.0001). Of these 7 patients, five (71%) regained awareness. CONCLUSIONS: The pupillary light-off reflex may be more sensitive to consciousness levels than the pupillary light reflex. The clinical implications of this finding seem worthy of further investigation, particularly regarding possible benefits for neuromonitoring and prognostication after brain injury.

Criteria for brain death in Denmark.

In 1990, the Danish brain death legislation was adopted by the Danish Parliament. Each year, around 100 patients in Denmark fulfil criteria for brain death/death by neurological criteria (BD/DNC). In this review of current Danish criteria including the indication for ancillary investigation, which in Denmark is digital subtraction angiography (DSA), we conclude that the time has come to revise the national BD/DNC criteria. We propose that visible anoxic-ischaemic encephalopathy on brain CT after cardiac arrest does not require evaluation by ancillary testing, and that CT-angiography can be used instead of DSA.

Confirmatory digital subtraction angiography after clinical brain death/death by neurological criteria: impact on number of donors and organ transplants.

Background: Demand for organs exceeds the number of transplants available, underscoring the need to optimize organ donation procedures. However, protocols for determining brain death (BD)/death by neurological criteria (DNC) vary considerably worldwide. In Denmark, digital subtraction angiography (DSA) is the only legally approved confirmatory test for diagnosing BD/DNC. We investigated the effect of the time delay caused by (repeat) confirmatory DSA on the number of organs donated by patients meeting clinical criteria for BD/DNC. We hypothesized that, first, patients investigated with ≥2 DSAs donate fewer organs than those investigated with a single DSA; second, radiological interpretation of DSA is subject to interrater variability; and third, residual intracranial circulation is inversely correlated with inotropic blood pressure support. Methods: All DSAs performed over a 7-year period as part of BD/DNC protocols at Rigshospitalet, Copenhagen University Hospital, Denmark, were included. Clinical data were extracted from electronic health records. DSAs were reinterpreted by an independent neurinterventionist blinded to the original radiological reports. Results: We identified 130 DSAs in 100 eligible patients. Patients with ≥2 DSAs (n = 20) donated fewer organs (1.7 +/- 1.6 SD) than patients undergoing a single DSA (n = 80, 2.6 +/- 1.7 organs, p = 0.03), and they became less often donors (n = 12, 60%) than patients with just 1 DSA (n = 65, 81.3%; p = 0.04). Interrater agreement of radiological DSA interpretation was 88.5% (Cohen's kappa = 0.76). Patients with self-maintained blood pressure had more often residual intracranial circulation (n = 13/26, 50%) than patients requiring inotropic support (n = 14/74, 18.9%; OR = 0.23, 95% CI [0.09-0.61]; p = 0.002). Discussion: In potential donors who fulfill clinical BD/DNC criteria, delays caused by repetition of confirmatory DSA result in lost donors and organ transplants. Self-maintained blood pressure at the time of clinical BD/DNC increases the odds for residual intracranial circulation, creating diagnostic uncertainty because radiological DSA interpretation is not uniform. We suggest that avoiding unnecessary repetition of confirmatory investigations like DSA may result in more organs donated.